DESCRIPTION: Pain afflicts 65-90 percent of cancer patients with disseminated disease. More than 40 percent of these patients receive inadequate treatment. A majority of oncologists identify concern about opioid side effects as a primary reason for inadequate pain control in cancer patients. Cognitive impairments are the most feared effects of opioids, yet the frequency and course of these effects are poorly described. The investigators propose to define and contrast the cognitive/affective, psychomotor and somatic side effect profiles of morphine and hydromorphone, which are the two most commonly prescribed opioids for cancer patients. The application describes two studies: a preliminary study and a primary double blind randomized, counterbalanced crossovers, placebo controlled laboratory study, bringing together clinical and laboratory expertise from psychology, neuropsychology, anesthesiology, pharmacology, and nursing. The preliminary aim is to establish equianalgesic levels of hydromorphone and morphine under conditions of sustained plasma opioid concentrations. Specific aims of the primary study are to: 1) determine whether side effects differ among morphine, hydromorphone and saline under conditions of sustained, equianalgesic plasma opioid concentrations; and 2) determine whether time to peak side effects is less when subjects receive hydromorphone (with no known active metabolite) than when subjects receive morphine for which time of peak effect is expected to correlate with plasma concentration of the active metabolite. In the preliminary study, six healthy volunteers will participate in four-hour tailored infusions of morphine and of hydromorphone at steady state plasma concentrations. In the primary study, twenty-four healthy volunteers will participate in three sessions requiring four-hour infusions of saline, morphine or hydromorphone at steady state plasma concentrations. At each session, the project will test repeated measures of pain, cognitive and psychomotor performance, subjective side effects, pupillometry, respiratory drive, and plasma concentration of opioid and active metabolite. Two primary hypotheses are proposed: 1) somatic side effects, cognitive/affective side effects and psychomotor effects differ when subjects receive morphine, hydromorphone and saline during steady state infusion; and 2) mean time to peak side effects when subjects receive hydromorphone is less than the mean time to peak side effects when subjects receive morphine; mean time to peak side effects when subjects receive morphine positively correlates with plasma concentration of the active metabolite morphine-6-glucuronide. The longer term aim is to use the proposed methodology to assess opioid effects in cancer patients.